While normal angiogenesis plays an important role in several processes including embryonic development, wound healing, and female reproductive function, undesirable or pathological angiogenesis has been associated with diseases such as diabetic retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma, asthma, cancer, and metastatic disease.
In adults, endothelial cells have a low proliferation index with the exception of tissue remodeling, such as wound healing and the female reproductive cycle, and adipogenesis. However, in pathological states as described above, endothelial cells are actively proliferating and organizing into vessels. Upon exposure to angiogenic stimuli with growth factors, including but not limited to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), endothelial cells re-enter the cell cycle, proliferate, migrate and organize into a three-dimensional network. It is now widely accepted that the ability of tumors to expand and metastasize is dependent upon the formation of this vascular network.
Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of a ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity that leads to phosphorylation of tyrosine residues on both the receptor and other intracellular proteins, leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies includes fms-like tyrosine kinase receptor, Flt or Flt1 (VEGFR-1), the kinase insert domain-containing receptor, KDR (also referred to as Flk-1 or VEGFR-2), and another fms-like tyrosine kinase receptor, Flt4 (VEGFR-3). Two of these related RTKs, Flt and KDR, have been shown to bind VEGF with high affinity. Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes. BEGF, along with acidic and basic fibroblast growth factor (aFGF and bFGF) have been identified as having in vitro endothelial cell growth promoting activity. By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, in contrast to that of the FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis and vascular permeability.
Binding of VEGF or bFGF to their corresponding receptor results in dimerization autophosphorylation on tyrosine residues and enzymatic activation. These phosphotyrosine residues serve as “docking” sites for specific downstream signaling molecules and enzymatic activation results in proliferation of endothelial cells. Disruption of these pathways should therefore result in inhibition of endothelial cell proliferation.
In addition to the aforementioned indications that can be treated with pyrrolotriazine compounds, it is noted that pyrrolotriazine compounds have been found to be useful as kinase inhibitors useful for inhibiting cell proliferation. Pyrrolotriazine compounds substituted with an acid group reportedly having sPLA2-inhibitory activity are disclosed in WO 01/14378 A1 to Shionogi & Co., Ltd, published Mar. 1, 2001 in Japanese. Recently discovered pyrrolotriazine compounds are disclosed, for example in commonly assigned U.S. patent application Ser. No. 09/573,929 filed May 18, 2000 and published Application U.S. 20040072832A1, filed Jul. 18, 2003. Other compounds suitable for inhibiting kinase activity are disclosed in commonly assigned U.S. Pat. No. 6,670,357. Pyrrolotriazine compounds having activity against signal transduction, e.g. against human epidermal growth factor receptor (HER) and associated glycoproteins have been disclosed in commonly assigned U.S. application Ser. No. 10/736,476 filed Dec. 15, 2003, as well as in the aforementioned application Ser. No. 09/573,929. Pyrrolotriazine compounds having activity against cMET anti-angiogenesis growth factor receptors are disclosed in commonly assigned U.S. Provisional Application Ser. No. 60/583,459, filed Jun. 28, 2004. Each of the foregoing mentioned commonly assigned patent documents, which may disclose various synthetic methods, is herein incorporated by reference in its entirety.
Other methods for manufacturing pyrrolotriazines are disclosed in commonly assigned U.S. application Ser. No. 10/289,010 filed Nov. 6, 2002 (now issued as U.S. Pat. No. 6,867,300), and U.S. Provisional Application Ser. No. 60/584,382, filed Jun. 30, 2004. These applications describe processes for producing pyrrolotriazines using amino pyrrole intermediates. According to U.S. Pat. No. 6,867,300, for example, amino pyrrole compounds may be formed by aminating a pyrrole using a haloamine such as chloroamine. This chloramine reagent is a gaseous reactant that can present handling difficulties during the manufacturing process. U.S. Provisional Application Ser. No. 60/584,382 discloses the formation of aminated pyrrole intermediates using other aminating agents.
Additional processes are needed to produce intermediates useful in forming pyrrolotriazines, and the target compounds themselves. There is a particular need for processes that utilize commercially available starting materials in order to minimize costs and/or reduce reliance on reactants that are inefficient or undesirable for manufacturing, while maintaining acceptable product yields.